US6288121B1 - Nimesulide topical formulations in the form of liquid crystals - Google Patents
Nimesulide topical formulations in the form of liquid crystals Download PDFInfo
- Publication number
- US6288121B1 US6288121B1 US09/355,734 US35573499A US6288121B1 US 6288121 B1 US6288121 B1 US 6288121B1 US 35573499 A US35573499 A US 35573499A US 6288121 B1 US6288121 B1 US 6288121B1
- Authority
- US
- United States
- Prior art keywords
- composition according
- weight
- nimesulide
- cetylstearyl
- phase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
Definitions
- the present invention relates to nimesulide topical formulations in the form of liquid crystals.
- Nimesulide is a known antiinflammatory agent whose therapeutical efficacy has been proved for some time, but which has the drawback of having unfavourable chemical-physical characteristics; the main obstacle to the use of nimesulide in topical formulations is in fact its insolubility in water and, on the other hand, its poor solubility in the solvents/raw materials usually employed in such formulations.
- nimesulide for the external use consist in dispersions of particles of the active ingredient throughout a component which, in the case of creams, comprises a hydorphilic polymer, and oily substance, a surfactant agent, a basic substance and water.
- liquid crystals present at the oil/water interface exert in fact a double effect in that they stabilize the emulsified system and control the release mechanism of the active ingredient, and therefore its bioavailability, thanks to the formation of a network system throughout which the active ingredient is homgeneously dispersed, thus involving unquestionable advantages compared with the conventional formulations containing water-in-oil (W/O) or oil-in-water (O/W) emulsions.
- W/O water-in-oil
- O/W oil-in-water
- cetylstearyl glycoside has been used as a non ionic oil in water (O/W) emulsifier, which, in the presence of a suitable aqueous phase, produces gel-structures by formation of liquid crystals.
- Cetylstearyl glycoside has safety and dermal tolerance characteristics ascribable to the natural origin of the compound itself; its hydrophilic portion derives, in fact, from the strong hydrolysis of starch and its lipophilic portion results from the hydrogenation of fatty acids derivatives of vegetable lipids.
- Cetylstearyl glycoside can be used at a concentration ranging from 3% to 10% by weight, preferably from 3% to 5%.
- the lipid phase of the emulsion consists of a caprylic/capric triglyceride, having a high carrier ability, thus giving the system sostantivity and emollient properties; caprylic/capric triglyceride can be used at a concentration ranging from 2% to 15% by weight, preferably from 2% to 6%.
- the lipid phase preferably contains a liquid natural wax, namely the jojoba oil, which, besides enhancing nimesulide dispersion capability, provides very good properties of smoothness, flowability, emollient properties, pleasantness and agreeableness of use.
- the jojoba oil can be used at a concentration ranging from 1% to 15% by weight, preferably from 3% to 7%.
- the emulsion also comprises as a “consistence factor”, cetylstearyl alcohol, which supplements the action of the cetylstearyl glycoside, due to the affinity between the two alkyl cetylstearyl chains, and contributing to the formation of the crystalline structure of the emulsion.
- Cetylstearyl alcohol can be used at a concentration ranging from 2% to 10% by weight, preferably from 2% to 5%.
- the formulation of the present invention can also contain emollients/humectants, such as cetyl ester 1-15% by weight, cholesterol 0.3-0.5% by weight, glycerin 1-30% by weight, isopropyl myristate 1-10% by weight, isopropyl palmitate 0.05-5,5% by weight, lecithin 1-20% by weight, lanolin alcohols 0.5-15% by weight, vaseline 4-95% by weight, soy lipids 1-20% by weight, anti-microbial preservatives, such as parabens mixtures, and chemical preservative, for example antioxidants such as tocopherol and lecithin, dermal absorption enhancers, such as propylene glycol 5-50% by weight, 2-pyrrolidone 0.1-10% by weight, pyrrolidone derivatives.
- emollients/humectants such as cetyl ester 1-15% by weight, cholesterol 0.3-0.5% by weight, glycerin 1-30% by weight,
- the amount of water in the formulations ranges from 40% to 95% by weight, whereas pH is preferably kept at about 5.5, for example by addition of citric acid, so as to warrant the chemical-physical stability of nimesulide.
- Nimesulide can be dispersed in a wide range of concentrations, preferably from 0 to 5% by weight.
- Said formulations can be prepared by means of a process comprising:
- phase containing the active ingredient nimesulide optionally jojoba oil, caprylic/capric triglyceride and optional preservatives;
- control and adjustment of pH preferably with citric acid.
- compositions of the invention proved to be well tolerated in animals.
- compositions of the invention have been tested using well-known pharmacological tests.
- the formulation was prepared at four nimesulide concentrations, i.e., 2%, 3%, 4%, 5% w/w, each concentration in 3 different 6 kg batches.
- the A and C phases were mixed separately in a blade mixer, with heating.
Abstract
Nimesulide topical formulations are provided in the form of liquid crystals. The emulsifier cetylstearyl glycoside is used, and constituents of the lipid phase such as caprylic/capric triglycerides and jojoba oil, consistence factors such as cetylstearyl alcohol. Also disclosed is a process for the preparation thereof. The formulations have advantages such as higher stability, better release and absorption of nimesulide, and a higher bioavailability of the active ingredient.
Description
1. Field of the Invention
2. Description of the Related Art
The present invention relates to nimesulide topical formulations in the form of liquid crystals.
Nimesulide is a known antiinflammatory agent whose therapeutical efficacy has been proved for some time, but which has the drawback of having unfavourable chemical-physical characteristics; the main obstacle to the use of nimesulide in topical formulations is in fact its insolubility in water and, on the other hand, its poor solubility in the solvents/raw materials usually employed in such formulations.
Some formulations of nimesulide for the external use are described in WO 96/11002; said formulations consist in dispersions of particles of the active ingredient throughout a component which, in the case of creams, comprises a hydorphilic polymer, and oily substance, a surfactant agent, a basic substance and water.
The application does not mention any possible use of liquid crystals for nimesulide topical formulations.
It has now been found that the emulsions containing liquid crystals, which are the object of the present invention, can be successfully used in nimesulide formulations for the topical use; liquid crystals present at the oil/water interface exert in fact a double effect in that they stabilize the emulsified system and control the release mechanism of the active ingredient, and therefore its bioavailability, thanks to the formation of a network system throughout which the active ingredient is homgeneously dispersed, thus involving unquestionable advantages compared with the conventional formulations containing water-in-oil (W/O) or oil-in-water (O/W) emulsions.
For the formulations of the present invention cetylstearyl glycoside has been used as a non ionic oil in water (O/W) emulsifier, which, in the presence of a suitable aqueous phase, produces gel-structures by formation of liquid crystals. Cetylstearyl glycoside has safety and dermal tolerance characteristics ascribable to the natural origin of the compound itself; its hydrophilic portion derives, in fact, from the strong hydrolysis of starch and its lipophilic portion results from the hydrogenation of fatty acids derivatives of vegetable lipids. Cetylstearyl glycoside can be used at a concentration ranging from 3% to 10% by weight, preferably from 3% to 5%.
The lipid phase of the emulsion consists of a caprylic/capric triglyceride, having a high carrier ability, thus giving the system sostantivity and emollient properties; caprylic/capric triglyceride can be used at a concentration ranging from 2% to 15% by weight, preferably from 2% to 6%.
Moreover, the lipid phase preferably contains a liquid natural wax, namely the jojoba oil, which, besides enhancing nimesulide dispersion capability, provides very good properties of smoothness, flowability, emollient properties, pleasantness and agreeableness of use. The jojoba oil can be used at a concentration ranging from 1% to 15% by weight, preferably from 3% to 7%.
The emulsion also comprises as a “consistence factor”, cetylstearyl alcohol, which supplements the action of the cetylstearyl glycoside, due to the affinity between the two alkyl cetylstearyl chains, and contributing to the formation of the crystalline structure of the emulsion.
Cetylstearyl alcohol can be used at a concentration ranging from 2% to 10% by weight, preferably from 2% to 5%.
The formulation of the present invention can also contain emollients/humectants, such as cetyl ester 1-15% by weight, cholesterol 0.3-0.5% by weight, glycerin 1-30% by weight, isopropyl myristate 1-10% by weight, isopropyl palmitate 0.05-5,5% by weight, lecithin 1-20% by weight, lanolin alcohols 0.5-15% by weight, vaseline 4-95% by weight, soy lipids 1-20% by weight, anti-microbial preservatives, such as parabens mixtures, and chemical preservative, for example antioxidants such as tocopherol and lecithin, dermal absorption enhancers, such as propylene glycol 5-50% by weight, 2-pyrrolidone 0.1-10% by weight, pyrrolidone derivatives.
The amount of water in the formulations ranges from 40% to 95% by weight, whereas pH is preferably kept at about 5.5, for example by addition of citric acid, so as to warrant the chemical-physical stability of nimesulide.
Nimesulide can be dispersed in a wide range of concentrations, preferably from 0 to 5% by weight.
The formulations based on liquid crystals of the invention have the following advantages:
improvement in the chemical-physical stability of the emulsion;
homogeneous distribution of the active ingredient in the crystalline structure;
control of the release and absorption of nimesulide;
increase in nimesulide bioavailability;
high compliance by the user.
Said formulations can be prepared by means of a process comprising:
hot preparation of the emulsion containing the two hydrophilic and lipophilic phases and the consistence factors;
separated preparation of the phase containing the active ingredient nimesulide optionally jojoba oil, caprylic/capric triglyceride and optional preservatives;
hot mixing of the two phases from the above steps, and subsequent cooling;
control and adjustment of pH, preferably with citric acid.
The compositions of the invention proved to be well tolerated in animals.
The efficacy of the compositions of the invention has been tested using well-known pharmacological tests.
The following examples further illustrate the invention.
| Phase | Ingredient | % w/w | ||
| Phase A | Purified water | q.s. | ||
| Glycerin | 3.00 | |||
| Phase B | Cetylstearyl glycoside | 5.00 | ||
| Cetyl alcohol | 2.00 | |||
| jojoba oil | 2.00 | |||
| Caprylic and capric | 1.20 | |||
| triglyceride | ||||
| Phase C | jojoba oil | 3.00 | ||
| Caprylic and capric | 1.80 | |||
| triglyceride | ||||
| Nimesulide | — | |||
| Parabens in phenoxy- | 1.00 | |||
| ethanol | ||||
| Tocopherol-Ascorbyl | 0.01 | |||
| palmitate soy lecithin- | ||||
| citric acid | ||||
| Phase D | Citric acid 5% sol. | q.s. | ||
The formulation was prepared at four nimesulide concentrations, i.e., 2%, 3%, 4%, 5% w/w, each concentration in 3 different 6 kg batches.
For the preparation, a Mambretti 25 kg turbodiffuser with cooling/heating water jacket, turbine, blades and vacuum was used.
The A and C phases were mixed separately in a blade mixer, with heating.
A mixture of methyl, ethyl and propyl p-hydroxybenzoates solubilized in phenoxyethanol and propylene glycol was used as preservative.
| % w/w | |||
| Water | 77.68 | ||
| Cetylstearyl glycoside | 5.00 | ||
| Jojoba esters | 5.00 | ||
| Caprylic/capric triglyceride | 3.00 | ||
| Glycerin | 3.00 | ||
| Cetyl alcohol | 2.00 | ||
| Nimesulide | 3.00 | ||
| Phenoxyethanol and methyl, | 1.00 | ||
| ethyl, propyl parabens | |||
| Perfluoropolymethylisopropyl ether | 0.30 | ||
| Tocopherol-ascorbyl palmitate- | 0.01 | ||
| lecithin-citric acid | |||
| Chemical- | |||||
| physical- | At | ||||
| characte- | prepara- | After 45 days | After 45 days | ||
| ristics | tion | at room temp. | at temp. = 40° C. | ||
| Aspect | Emulsion | Emulsion | Emulsion | ||
| compact | compact | compact | |||
| slightly | slightly | slightly | |||
| yellowish | yellowish | yellowish | |||
| pH | 5.13 | 5.00 | 4.92 | ||
No traces of separation or decrease in viscosity were observed.
| % w/w | |||
| Water | 77.98 | ||
| Cetylstearyl glycoside | 5.00 | ||
| Jojoba esters | 5.00 | ||
| Caprylic/capric triglyceride | 3.00 | ||
| Glycerin | 3.00 | ||
| Cetyl alcohol | 2.00 | ||
| Nimesulide | 3.00 | ||
| Phenoxyethanol and methyl, | 1.00 | ||
| ethyl, propyl parabens | |||
| Tocopherol-ascorbyl palmitate- | 0.01 | ||
| lecithin-citric acid | |||
| Citric acid 5% sol. | 0.0066 | ||
| Chemical- | |||||
| physical- | At | ||||
| characte- | prepara- | After 45 days | After 45 days | ||
| ristics | tion | at room temp. | at temp. = 40° C. | ||
| Aspect | Emulsion | Emulsion | Emulsion | ||
| compact | compact | compact | |||
| slightly | slightly | slightly | |||
| yellowish | yellowish | yellowish | |||
| pH | 5.08 | 5.02 | 4.90 | ||
No traces of separation or decrease in viscosity were observed.
Claims (13)
1. A nimesulide composition for topical administration, said composition comprising nimesulide dispersed in a liquid crystal-containing emulsion comprising a lipid phase containing caprylic and/or capric triglycerides, an aqueous phase, cetylstearyl glycoside and cetylstearyl alcohol, wherein said cetylstearyl glycoside causes formation of liquid crystals at an oil/aqueous interface of said lipid phase and said aqueous phase, and wherein said lipid phase optionally contains jojoba oil.
2. The composition according to claim 1, wherein said triglycerides of the lipid phase are present at a concentration ranging form 2% to 15% by weight.
3. The composition according to claim 2 in which said concentration ranges from 2% to 6% by weight.
4. The composition according to claim 1, wherein the jojoba oil is present at a concentration ranging from 1% to 15% by weight.
5. The composition according to claim 1, wherein the cetylstearyl glycoside is present at a concentration ranging from 3% to 10% by weight.
6. The composition according to claim 5 in which said concentration ranges from 3% to 5% by weight.
7. The composition according to claim 1, wherein cetylstearyl alcohol is present at a concentration ranging from 2% to 10% by weight.
8. The composition according to claim 7 in which said concentration ranges from 2% to 5% by weight.
9. The composition according to claim 1, further comprising additives selected from emollients, humectants, absorption enhancers, preservatives.
10. The composition according to claim 9 in which the wetting agent is glycerin.
11. The composition according to claim 9 in which the preservatives are mixtures of parabens, tocopherol and lecithin.
12. The composition according to claim 1 in which the active ingredient nimesulide is present at a concentration up to 5% by weight.
13. A process for preparing the composition of claim 1, which comprises:
preparing an emulsion containing two hydrophilic phases and a lipophilic phase and cetylstearyl glycoside;
separately preparing a phase containing nimesulide, caprylic/capric triglycerides and optional preservatives, and optional jojoba oil;
mixing the phases from the above steps; and
adjusting pH of the resulting emulsion.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI97A0407 | 1997-02-25 | ||
| IT97MI000407A IT1289972B1 (en) | 1997-02-25 | 1997-02-25 | TOPICAL FORMULATIONS OF NIMESULIDE IN THE FORM OF LIQUID CRYSTAL SYSTEMS |
| PCT/EP1998/000896 WO1998037868A2 (en) | 1997-02-25 | 1998-02-17 | Nimesulide topical formulations in the form of liquid crystals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US6288121B1 true US6288121B1 (en) | 2001-09-11 |
Family
ID=11376171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/355,734 Expired - Fee Related US6288121B1 (en) | 1997-02-25 | 1998-02-17 | Nimesulide topical formulations in the form of liquid crystals |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US6288121B1 (en) |
| EP (1) | EP1007001B1 (en) |
| AT (1) | ATE287701T1 (en) |
| AU (1) | AU6720498A (en) |
| DE (1) | DE69828797D1 (en) |
| IT (1) | IT1289972B1 (en) |
| PT (1) | PT1007001E (en) |
| WO (1) | WO1998037868A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6734944B1 (en) * | 1999-04-28 | 2004-05-11 | International Business Machines Corporation | Liquid crystal display |
| US20150147403A1 (en) * | 2012-06-01 | 2015-05-28 | Galderma Research & Development | Dermatological composition comprising oleosomes and retinoids, process for preparing the same and use thereof |
| US10925822B2 (en) | 2012-06-01 | 2021-02-23 | Galderma Research & Development | Process for preparing a dermatological composition comprising oleosomes |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU718356B2 (en) * | 1998-01-12 | 2000-04-13 | Panacea Biotec Limited | A parenteral water-miscible non-intensely coloured injectable composition of non-steroidal anit-inflammatory drugs |
| GB2340751B (en) * | 1998-08-12 | 2003-11-05 | Edko Trading Representation | Pharmaceutical compositions |
| CN105384664A (en) * | 2015-10-15 | 2016-03-09 | 中国药科大学 | Novel crystal habit of nimesulide |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0087062A2 (en) | 1982-02-16 | 1983-08-31 | Dolorgiet GmbH & Co. KG | Pharmaceutical composition containing ibuprofen for external application, and method of preparing the same |
| US5283261A (en) * | 1991-09-20 | 1994-02-01 | Lpb Istituto Farmaceutico | Use of nimesulide in the treatment of cataract |
| DE4320119A1 (en) | 1993-06-18 | 1994-12-22 | Henkel Kgaa | Liquid crystalline aqueous surfactant preparation |
| WO1996011002A1 (en) | 1994-10-05 | 1996-04-18 | Hisamitsu Pharmaceutical Co., Inc. | Antiinflammatory agent for external use |
| US5688829A (en) * | 1995-07-25 | 1997-11-18 | Panacea Biotec Limited | Therapeutic injectable analgesic composition containing nimesulide and a process for the manufacture thereof |
| US5942216A (en) * | 1994-12-06 | 1999-08-24 | Helene Curtis, Inc. | Water-in-oil-in-water compositions |
| US6017932A (en) * | 1996-12-12 | 2000-01-25 | Panacea Biotec Limited | Pharmaceutical compositions containing at least one NSAID having increased bioavailability |
| US6136804A (en) * | 1998-03-13 | 2000-10-24 | Merck & Co., Inc. | Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions |
| US6194462B1 (en) * | 1997-04-24 | 2001-02-27 | Errekappa Euroterapici S.P.A. | Pharmaceutical preparation containing nimesulide for oral administration |
-
1997
- 1997-02-25 IT IT97MI000407A patent/IT1289972B1/en active IP Right Grant
-
1998
- 1998-02-17 PT PT98912317T patent/PT1007001E/en unknown
- 1998-02-17 AU AU67204/98A patent/AU6720498A/en not_active Abandoned
- 1998-02-17 US US09/355,734 patent/US6288121B1/en not_active Expired - Fee Related
- 1998-02-17 WO PCT/EP1998/000896 patent/WO1998037868A2/en active IP Right Grant
- 1998-02-17 DE DE69828797T patent/DE69828797D1/en not_active Expired - Fee Related
- 1998-02-17 AT AT98912317T patent/ATE287701T1/en not_active IP Right Cessation
- 1998-02-17 EP EP98912317A patent/EP1007001B1/en not_active Expired - Lifetime
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0087062A2 (en) | 1982-02-16 | 1983-08-31 | Dolorgiet GmbH & Co. KG | Pharmaceutical composition containing ibuprofen for external application, and method of preparing the same |
| US5283261A (en) * | 1991-09-20 | 1994-02-01 | Lpb Istituto Farmaceutico | Use of nimesulide in the treatment of cataract |
| DE4320119A1 (en) | 1993-06-18 | 1994-12-22 | Henkel Kgaa | Liquid crystalline aqueous surfactant preparation |
| WO1996011002A1 (en) | 1994-10-05 | 1996-04-18 | Hisamitsu Pharmaceutical Co., Inc. | Antiinflammatory agent for external use |
| EP0782855A1 (en) | 1994-10-05 | 1997-07-09 | Helsinn Healthcare S.A. | Antiinflammatory agent for external use |
| US5837735A (en) * | 1994-10-05 | 1998-11-17 | Helsinn Healthcare S.A. | Antiinflammatory agent for external use |
| US5942216A (en) * | 1994-12-06 | 1999-08-24 | Helene Curtis, Inc. | Water-in-oil-in-water compositions |
| US5688829A (en) * | 1995-07-25 | 1997-11-18 | Panacea Biotec Limited | Therapeutic injectable analgesic composition containing nimesulide and a process for the manufacture thereof |
| US5716609A (en) * | 1995-07-25 | 1998-02-10 | Panacea Biotec Limited | Therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and a process for the manufacture thereof |
| US6017932A (en) * | 1996-12-12 | 2000-01-25 | Panacea Biotec Limited | Pharmaceutical compositions containing at least one NSAID having increased bioavailability |
| US6194462B1 (en) * | 1997-04-24 | 2001-02-27 | Errekappa Euroterapici S.P.A. | Pharmaceutical preparation containing nimesulide for oral administration |
| US6136804A (en) * | 1998-03-13 | 2000-10-24 | Merck & Co., Inc. | Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6734944B1 (en) * | 1999-04-28 | 2004-05-11 | International Business Machines Corporation | Liquid crystal display |
| US20150147403A1 (en) * | 2012-06-01 | 2015-05-28 | Galderma Research & Development | Dermatological composition comprising oleosomes and retinoids, process for preparing the same and use thereof |
| US10925822B2 (en) | 2012-06-01 | 2021-02-23 | Galderma Research & Development | Process for preparing a dermatological composition comprising oleosomes |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998037868A3 (en) | 1998-12-10 |
| PT1007001E (en) | 2005-05-31 |
| ATE287701T1 (en) | 2005-02-15 |
| ITMI970407A1 (en) | 1998-08-25 |
| IT1289972B1 (en) | 1998-10-19 |
| EP1007001A2 (en) | 2000-06-14 |
| EP1007001B1 (en) | 2005-01-26 |
| WO1998037868A2 (en) | 1998-09-03 |
| AU6720498A (en) | 1998-09-18 |
| DE69828797D1 (en) | 2005-03-03 |
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Owner name: HELSINN HEALTHCARE S.A., SWITZERLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BADER, STEFANO;MONTI, TIZIANA;HAUSERMANN, ENRIQUE;REEL/FRAME:010352/0545;SIGNING DATES FROM 19990527 TO 19990721 |
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| FPAY | Fee payment |
Year of fee payment: 4 |
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| FPAY | Fee payment |
Year of fee payment: 8 |
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| REMI | Maintenance fee reminder mailed | ||
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| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
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| FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20130911 |